Early diagnosis of hereditary cancer syndromes at primary care enables early intervention and better management of both patients and their families. The National Cancer Centre Singapore shares what to look out for when it comes to some of the most common hereditary cancers in Singapore.
INTRODUCTION
General practitioners (GPs) are usually the first point of contact for patients with hereditary cancer syndromes. Though rare, accounting for roughly 5-10% of all cancers (Figure 1), a timely diagnosis is important – as not only do patients require long-term care from a young age, but their relatives also require management.1
In the past decades, enormous strides have been made to unravel the genetic basis of cancer, and this knowledge has been used to develop targeted treatments for hereditary forms of cancer.
Germline genetic testing for patients and their families with suspected hereditary cancer syndromes is therefore a vital component of the practice of preventative oncology and should become routine clinical care.
Some of the most common hereditary cancer syndromes in Singapore are:
Hereditary breast and ovarian cancer syndrome
Lynch syndrome
Familial adenomatous polyposis
GPs play an important role in enabling early intervention and better management of these patients.
Top Three Hereditary Cancer Syndromes
1. HEREDITARY BREAST AND OVARIAN CANCER
Hereditary breast and ovarian cancer syndrome (HBOC) is one of the most common hereditary cancer syndromes. It follows autosomal dominant inheritance – which means that inheriting one copy of a mutated gene, either from the mother or father, is sufficient to increase the risk of cancer as children have a 50% chance of inheriting the faulty gene.
The faulty gene is associated with early-onset breast and ovarian cancer, but individuals with HBOC are also at higher risk of developing male breast cancer, prostate cancer, pancreatic cancer and melanoma.2 It accounts for 5-10% of all breast cancer cases, 10-15% of ovarian cancer cases and 3-5% of pancreatic and prostate cancers.3-6
Causes
HBOC is primarily caused by pathogenic variants in the BRCA1 and BRCA2 genes which play a crucial role in repairing damaged DNA.1, 2, 7, 8 There are other genes associated with HBOC, including but not limited to PALB2, TP53, PTEN and RAD51C/D.2, 9, 10 These genes encode for components of multi-protein complexes (e.g., PALB2 is a partner and localiser of BRCA2) and are vital to repairing DNA double-strand breaks.
Prevalence
The SG10K_Health study by PRECISE, which aims to improve patient outcomes by identifying genetic factors predisposing Singaporeans to prevalent disease conditions, revealed a high prevalence of HBOC in Singapore.28
Roughly 1 in 150 Singaporeans carry a pathogenic variant of HBOC, compared to an estimated prevalence of 1 in 400-500 outside of Singapore, depending on the population (Figure 2A).28-30
Of those at risk in the Singapore population, the most common pathogenic variants were BRCA2 and BRCA1 carriers, followed by PALB2 carriers.28
Cancer risk
Managing cancer risk
Individuals at risk require earlier and more frequent surveillance throughout their lives to prevent cancer. For example, asymptomatic BRCA1/2 carriers are recommended to commence annual breast mammograms and/or MRI from age 25 (or 5-10 years prior to the earliest diagnosis in the family, whichever comes first) as opposed to bi-annual mammograms from age 50 for the general population.
2. LYNCH SYNDROME
Lynch syndrome (LS) is the most common cause of hereditary colon cancer.31
Following autosomal dominant inheritance, it is associated with early-age onset colorectal cancer without polyposis; endometrial, ovarian, gastric, small-bowel, renal pelvis, pancreatic and bladder cancers; and other cancers.32 It accounts for around 3% of all colorectal cancer diagnoses.
Causes
It is caused by pathogenic variants in: 33, 34
- Mismatch repair (MMR) genes: MLH1, MSH2, MSH6, PMS2
MMR is a system that recognises and repairs errors that occur during DNA replication and plays a crucial role in maintaining genomic stability.35 - Epigenetic regulator EPCAM
EPCAM pathogenic variants result in silencing of the MMR gene MSH2, thereby disturbing the MMR system.36
Prevalence
In Singapore, around 1 in 530 individuals have a pathogenic variant of LS (Figure 2B) compared to around 1 in 300 outside of Singapore, depending on the population.28, 37
Of those at risk in the Singapore population, the most common pathogenic variants were MSH6 and PMS2 carriers, followed by MLH1 carriers.28
Cancer risk
The lifetime risk for the development of cancer will depend on the pathogenic variant, as well as the individual’s biological sex.
Managing cancer risk
These differences in cancer risk support the use of gene-specific screening and surveillance recommendations for LS.
For example, individuals with a MLH1 pathogenic variant should be offered earlier and more frequent colonoscopies than a PMS2 carrier who can start screening later.
3. FAMILIAL ADENOMATOUS POLYPOSIS
Familial adenomatous polyposis (FAP) is a common hereditary cancer syndrome with high penetrance.
Types and polyp/cancer risk
Classic FAP
Classic FAP is characterised by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, often starting in the teenage years or early adulthood. If left untreated, these polyps have a nearly 100% chance of becoming cancerous by the age of 40.45
In addition to colorectal cancer, people with FAP may also develop polyps in other parts of the gastrointestinal tract.
Attenuated familial adenomatous polyposis (AFAP)
AFAP is a variant of FAP, but is characterised by a milder presentation, typically with fewer polyps and a later onset of symptoms. In AFAP, affected individuals usually develop fewer than 100 polyps in the colon and rectum, as opposed to the hundreds to thousands seen in classic FAP.
Additionally, the polyps tend to develop later in life, often in one’s 30s or 40s, compared to the teenage or early adulthood onset seen in classic FAP.46
Causes
FAP and AFAP are caused by pathogenic variants in the adenomatous polyposis coli (APC) gene and are also inherited in an autosomal dominant pattern.
The APC gene plays a crucial role in regulating cell growth and division, particularly in the lining of the colon and rectum. Its main function is to act as a tumour suppressor. The specific genetic mutations present in the APC gene determine whether an individual has AFAP or classic FAP.45
Cancer risk
Managing polyp/cancer risk
Although FAP is not as prevalent as HBOC and LS in Singapore, genetic testing and counselling are still important so that individuals can understand their risks, to make informed decisions about screening and treatment options.
It is important for GPs to be aware of these common hereditary cancer syndromes as they can play a key role in detection – which in turn enables early intervention and better management for these patients. Find out more about what GPs should look out for and how to refer for genetic testing in the next issue of Defining Med, in the article It’s All in Your Genes (Part 2): The Role and Importance of Genetic Testing for Cancer Risk GPs Should Know About. To refer a patient with a cancer predisposition syndrome to any of CGS' research programmes, partner with us or learn more about our educational and training opportunities, GPs can contact us at: Cancer Genetics Service, National Cancer Centre Singapore
Tel: 6436 8000 / 6436 8288
Email: [email protected]
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CANCER GENETICS SERVICE
The Cancer Genetics Service (CGS) at National Cancer Centre Singapore is celebrating its 10th anniversary this year.
This marks a decade of delivering individualised patient care, participating in clinical research as well as engaging in education and campaigns.
Patient care
CGS provides individualised cancer risk assessment, genetic counselling and testing services for a broad range of genetic and hereditary conditions. This helps tailor clinical management and treatment for the individual and paves the way towards personalised medicine. CGS serves as a single unified platform coordinating patient care, research and education of genomic medicine.
Clinical research
CGS actively contributes to research on a national and international scale. It has multiple ongoing research studies to identify novel pathogenic gene variants that predispose individuals to cancer. It is also involved in health services research to understand the psychosocial impact of hereditary cancer syndromes, and is exploring the use of outreach methods to improve accessibility for cancer genetics testing. CGS is also interested in the design of novel drugs tailored for gene-directed targeted treatment of patients with metastatic cancer.
Education
The team at CGS are strong advocates of raising awareness and providing education to both the public and healthcare professionals. CGS regularly conducts outreach programmes to educate the public on hereditary cancers. This is often done in conjunction with its annual ‘Jeans for Genes’ campaign in April to raise awareness for such cancers.
CGS contributes knowledge through various channels which include GP education forums, multidisciplinary tumour board meetings, clinical rotation training, as well as local and international workshops, conferences and lectures.
In addition to training international aspiring genetics professionals, the service is actively involved in the training of medical students, doctors and nurses – where CGS is regarded as a regional and international centre for cancer genetics training.
Campaigns and events
The ‘Living with’ series of events are specially organised for patients and their families living with a hereditary cancer syndrome that predisposes them to certain cancer risks.
These events are important in facilitating support networks for patients and their families. Connecting with others facing similar challenges can provide emotional support and practical advice, improving coping mechanisms and resilience.
Our yearly Hereditary Cancer Syndrome Awareness and Family Days include:
- March: Living with LS
- May: Living with Li-Fraumeni Syndrome
- May: Living with Neurofibromatosis
- October: Living with HBOC
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Rebecca Caeser
Senior Research Fellow, Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore
Ms Rebecca Caeser is a Senior Research Fellow at the National Cancer Centre Singapore and has ten years of research experience in oncology. She received her PhD from the University of Cambridge before joining the Memorial Sloan Kettering Cancer Centre in New York as a Postdoctoral Researcher. She has a strong interest in precision health, with the aim of improving patients’ health on a population level.
Tasmyn Scriven
Genetic Counsellor, Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore
Ms Tasmyn Scriven is a Genetic Counsellor at the National Cancer Centre Singapore. She received her Master of Science (Medicine) in Genetic Counselling at the University of Witwatersrand, South Africa. Ms Scriven has a passion for empowering patients with knowledge and psychosocial support as they navigate their cancer journey.
Assoc Prof Joanne Ngeow
Head & Senior Consultant, Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore;
Deputy Head & Service Chief, Cancer Genetics, SingHealth Duke-NUS Genomic Medicine Centre;
Senior Consultant, Paediatric Brain and Solid Tumour Programme & Visiting Consultant, KK Breast Centre, KK Women’s and Children’s Hospital
Associate Professor Joanne Ngeow is a Senior Consultant in the Division of Medical Oncology, National Cancer Centre Singapore (NCCS) and Associate Professor at Lee Kong Chian School of Medicine, Nanyang Technological University. She heads the NCCS Cancer Genetics Service with an academic interest in hereditary cancer syndromes and translational cancer genetics. Her current clinical and research focus revolves around understanding cancer predisposition by studying cancers clustered in families, young adults with cancers and patients with multiple or rare cancers.
